Interest in the percutaneous or transdermal delivery of peptides, proteins, and other macromolecules, such as oligonucleotides, to the human body continues to grow with the increasing number of medically useful peptides and proteins becoming available in large quantities and pure form. The transdermal delivery of peptides and proteins still faces significant problems. In many instances, the rate of delivery or flux of polypeptides through the skin is insufficient to produce a desired therapeutic effect due to the low transdermal permeability coefficient of macromolecules and the binding of the polypeptides to the skin. In addition, polypeptides and proteins are easily degraded during and after penetration into the skin, prior to reaching target cells. Likewise, the passive transdermal flux of many low molecular weight compounds is too limited to be therapeutically effective.
One method of increasing the transdermal delivery of agents relies on the application of an electric current across the body surface referred to as “electrotransport.” “Electrotransport” refers generally to the passage of a beneficial agent, e.g., a drug or drug precursor, through a body surface, such as skin, mucous membranes, nails, and the like. The transport of the agent is induced or enhanced by the application of an electrical potential, which results in the application of electric current, which delivers or enhances delivery of the agent. The electrotransport of agents through a body surface may be attained in various manners. One widely used electrotransport process, iontophoresis involves the electrically induced transport of charged ions. Electroosmosis, another type of electrotransport process, involves the movement of a solvent with the agent through a membrane under the influence of an electric field. Electroporation, still another type of electrotransport, involves the passage of an agent through pores formed by applying a high voltage electrical pulse to a membrane. In many instances, more than one of these processes may be occurring simultaneously to a different extent. Accordingly, the term “electrotransport” is given herein its broadest possible interpretation, to include the electrically induced or enhanced transport of at least one charged or uncharged agent, or mixtures thereof, regardless of the specific mechanism or mechanisms by which the agent is actually being transported. Electrotransport delivery generally increases agent delivery and reduces polypeptide degradation during transdermal delivery.
Another method of increasing the agent flux involves pre-treating the skin with, or co-delivering with the beneficial agent, a skin permeation enhancer. A permeation enhancer substance, when applied to a body surface through which the agent is delivered, enhances its flux therethrough such as by increasing the permselectivity and/or permeability of the body surface, reducing the electrical resistance of the body surface to the passage of the agent and/or creating hydrophilic pathways through the body surface in the case of transdermal electrotransport delivery, and/or reducing the degradation of the agent.
There also have been many attempts to mechanically penetrate or disrupt the skin in order to enhance the transdermal flux. See for example, U.S. Pat. No. 3,814,097 issued to Ganderton, et al., U.S. Pat. No. 5,279,544 issued to Gross, et al., U.S. Pat. No. 5,250,023 issued to Lee, et al., U.S. Pat. No. 3,964,482 issued to Gerstel, et al., Reissue 25,637 issued to Kravitz, et al., and PCT Publication Nos. WO 96/37155, WO 96/37256, WO 96/17648, WO 97103718, WO 98/11937, WO 98/00193, WO 97/48440, WO 97148441, and WO 97/48442. These devices use piercing elements of various shapes and sizes to pierce the outermost layer (i.e., the stratum corneum) of the skin. The piercing elements disclosed in these references generally extend perpendicularly from a thin, flat member, such as a pad or sheet. The piercing elements in some of these devices are extremely small, some having dimensions (i.e., a microblade length and width) of only about 25-400 μm and a microblade thickness of only about 5-50 μm. These tiny piercing/cutting elements are meant to make correspondingly small microslits/microcuts in the stratum corneum for enhanced transdermal agent delivery therethrough.
A limitation on devices having such tiny skin penetrating elements is that the elastic properties of the patient's skin 30 allow the skin to conform around the individual skin penetrating elements 32 significantly before those elements actually breach the skin as shown in FIG. 1. In order to overcome this conforming effect and offsetting the condition in which the patient's skin is slack between the penetrating elements 32 as shown in FIG. 2, the skin penetrating elements are sometimes designed to be four to five times longer than what is necessary for the desired penetration depth. The conformance of the skin around the individual skin penetrating elements can also diminish the advantage of a sharp tip on each element because the entire bottom edge of the skin penetrating element is pushed against the skin, as can be seen in FIG. 1. In addition, the tissue layers under the stratum corneum can cause uneven distribution of the total force applied by allowing more conformance around some microprotrusions than others, resulting in several different local pressures across the site. As can be seen in FIG. 2, this results in nonuniform penetration depth across the site by the individual skin penetrating elements which each penetrate the skin to a different depth 35. It is desirable to produce devices for more reliable penetration for producing more uniform flux of an agent being delivered.